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Ataxia telangiectasia mutated germline pathogenic variant in adrenocortical carcinoma
Madeline B Torres1, Laurence P Diggs2, Jun S Wei3
1Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States; Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, United States.
Background:
Adrenocortical carcinoma (ACC) is a rare malignancy arising from the adrenal cortex. ACC carries a dismal prognosis and surgery offers the only chance for a cure. Germline pathogenic variants among certain oncogenes have been implicated in ACC. Here, we report the first case of ACC in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene.
Patients And Methods:
A 56-year-old Caucasian woman with biopsy proven ACC deemed unresectable and treated with etoposide, doxorubicin and cisplatin (EDP), and mitotane presented to our institution for evaluation. The tumor specimen was examined pathologically, and genetic analyses were performed on the tumor and germline using next-generation sequencing.
Results:
Pathologic evaluation revealed an 18.0 × 14.0 × 9.0 cm low-grade ACC with tumor free resection margins. Immunohistochemistry stained for inhibin, melan-A, and chromogranin. ClinOmics analysis revealed a germline pathogenic deletion mutation of one nucleotide in ATM is denoted as c.1215delT at the cDNA level and p.Asn405LysfsX15 (N405KfsX15) at the protein level. Genomic analysis of the tumor showed loss of heterozygosity (LOH) of chromosome 11 on which the ATM resides.
Conclusion:
ACC is an aggressive malignancy for which surgical resection currently offers the only curative option. Here we report a heterozygous loss-of-function mutation in germline DNA and LOH of ATM in tumor in an ACC patient, a classic two-hit scenario in a well-known cancer suppresser gene, suggesting a pathogenic role of the ATM gene in certain ACC cases.
Insights
This study reports the first case of adrenocortical carcinoma (ACC) in a patient with a pathogenic variant in the Ataxia Telangiectasia Mutated (ATM) gene. This finding suggests a potential role for ATM gene mutations in ACC development.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Adrenocortical carcinoma (ACC) is a rare and aggressive adrenal cortex malignancy with a poor prognosis.
- Surgical resection is the only curative treatment for ACC.
- Germline pathogenic variants in oncogenes are implicated in ACC development.
Observation:
- A 56-year-old woman with unresectable ACC received etoposide, doxorubicin, cisplatin (EDP), and mitotane treatment.
- Next-generation sequencing identified a germline pathogenic deletion mutation in the Ataxia Telangiectasia Mutated (ATM) gene (c.1215delT; p.Asn405LysfsX15).
- Tumor genomic analysis revealed loss of heterozygosity (LOH) of chromosome 11, where the ATM gene is located.
Findings:
- The patient had a low-grade ACC with tumor-free resection margins.
- A heterozygous loss-of-function mutation in germline ATM DNA and LOH of ATM in the tumor were identified.
- This represents a classic two-hit scenario in a known tumor suppressor gene.
Implications:
- The ATM gene may play a pathogenic role in a subset of adrenocortical carcinoma cases.
- This discovery could lead to new diagnostic or therapeutic strategies targeting ATM in ACC.
- Further research is warranted to elucidate the specific mechanisms by which ATM mutations contribute to ACC.
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